Abstract
Compelling evidence suggests that benign prostatic hyperplasia (BPH) development involves accumulation of mesenchymal-like cells derived from the prostatic epithelium by epithelial-mesenchymal transition (EMT). Transforming growth factor (TGF)-β induces EMT phenotypes with low E-cadherin and high vimentin expression in prostatic epithelial cells. Here we report that LPS/TLR4 signalling induces down-regulation of the bone morphogenic protein and activin membrane-bound inhibitor (BAMBI), which enhances TGF-β signalling in the EMT process during prostatic hyperplasia. Additionally, we found that the mean TLR4 staining score was significantly higher in BPH tissues with inflammation compared with BPH tissues without inflammation (5.13 ± 1.21 and 2.96 ± 0.73, respectively; P < 0.001). Moreover, patients with inflammatory infiltrate were more likely to have a higher age (P = 0.020), BMI (P = 0.026), prostate volume (P = 0.024), total IPSS score (P = 0.009) and IPSS-S (P < 0.001). Pearson’s correlation coefficient and multiple regression analyses demonstrated that TLR4 mRNA expression level was significantly positively associated with age, BMI, serum PSA levels, urgency and nocturia subscores of IPSS in the inflammatory group. These findings provide new insights into the TLR4-amplified EMT process and the association between TLR4 levels and storage LUTS, suggesting chronic inflammation as vital to the pathogenesis of BPH.
Highlights
Prostate epithelial cells secrete inflammatory cytokines that lead to the activation of signalling pathways that regulate cell proliferation, apoptosis and differentiation[6,7]
Western blot and qPCR analysis showed that LPS 100 ng/ml or 0.1 ng/ml Transforming growth factor (TGF)-β 1 alone had no significant effect on E-cadherin or vimentin mRNA and protein expression
Its incidence gradually increases with age; more than two-thirds of men aged over 50 have histological evidence of benign prostatic hyperplasia (BPH) and about half of the male population older than 50 years suffers from BPH-associated lower urinary tract symptoms (LUTS) symptoms, such as urgency, frequency and retention[25,26]
Summary
Prostate epithelial cells secrete inflammatory cytokines that lead to the activation of signalling pathways that regulate cell proliferation, apoptosis and differentiation[6,7]. To our knowledge, there are few reports concerning the TLR4-mediated signalling pathway in prostatic epithelial cells. Recent evidence suggests that BPH development involves accumulation of mesenchymal-like cells derived from the prostatic epithelium by epithelial-mesenchymal transition (EMT)[14,15,16]. We report that BAMBI acts as a regulator between LPS/TLR4 signalling and TGF-β-induced EMT in vitro during prostatic hyperplasia. We explored a hypothetical molecular mechanism underlying inflammatory BPH, namely that TLR4-dependent downregulation of BAMBI might be an important mechanism of TLR4 activation intensifying TGF-β-mediated EMT. We further examined the correlation between TLR4 mRNA expression and clinical findings, including the severity of lower urinary tract symptoms (LUTS), in the prostate of BPH patients with inflammatory infiltrate
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